The present invention relates to novel substituted histidine compounds useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention inhibit farnesyl transferase enzyme which activates ras proteins which in turn activate cellular division. More particularly, the novel compounds of the present invention are useful in the treatment of proliferative diseases such as, for example, cancer, restenosis, and psoriasis, and as antiviral agents.
Ras protein (or p21) has been examined extensively because mutant forms are found in 20% of most types of human cancer and greater than 50% of colon and pancreatic carcinomas (Gibbs J. B., Cell, 65:1 (1991), Cartwright T., et al., Chimica. Oggi., 10:26 (1992)). These mutant ras proteins are deficient in the capability for feedback regulation that is present in native ras and this deficiency is associated with their oncogenic action since the ability to stimulate normal cell division cannot be controlled by the normal endogenous regulatory cofactors. The recent discovery that the transforming activity of mutant ras is critically dependent on post-translational modifications (Gibbs J., et al., Microbiol. Rev., 53:171 (1989)) has unveiled an important aspect of ras function and identified novel prospects for cancer therapy.
In addition to cancer, there are other conditions of uncontrolled cellular proliferation that may be related to excessive expression and/or function of native ras proteins. Post-surgical vascular restenosis is such a condition. The use of various surgical revascularization techniques such as saphenous vein bypass grafting, endarterectomy and transluminal coronary angioplasty is often accompanied by complications due to uncontrolled growth of neointimal tissue, known as restenosis. The biochemical causes of restenosis are poorly understood and numerous growth factors and protooncogenes have been implicated (Naftilan A. J., et al., Hypertension, 13:706 (1989) and J. Clin. Invest., 83:1419; Gibbons G. H., et al., Hypertension, 14:358 (1989); Satoh T., et al., Mollec. Cell. Biol., 13:3706 (1993)). The fact that ras proteins are known to be involved in cell division processes makes them a candidate for intervention in many situations where cells are dividing uncontrollably. In direct analogy to the inhibition of mutant ras related cancer, blockade of ras dependent processes has the potential to reduce or eliminate the inappropriate tissue proliferation associated with restenosis, particularly in those instances where normal ras expression and/or function is exaggerated by growth stimulatory factors.
Ras functioning is dependent upon the modification of the proteins in order to associate with the inner face of plasma membranes. Unlike other membrane-associated proteins, ras proteins lack conventional transmembrane or hydrophobic sequences and are initially synthesized in a cytosol soluble form. Ras protein membrane association is triggered by a series of post-translational processing steps that are signaled by a carboxyl terminal amino acid consensus sequence that is recognized by protein farnesyltransferase (PFT). This consensus sequence consists of a cysteine residue located four amino acids from the carboxyl terminus, followed by two lipophilic amino acids and the C-terminal residue. The sulfhydryl group of the cysteine residue is alkylated by farnesylpyrophosphate in a reaction that is catalyzed by protein farnesyltransferase. Following prenylation, the C-terminal three amino acids are cleaved by an endoprotease and the newly exposed alpha-carboxyl group of the prenylated cysteine is methylated by a methyl transferase. The enzymatic processing of ras proteins that begins with farnesylation enables the protein to associate with the cell membrane. Mutational analysis of oncogenic ras proteins indicate that these post-translational modifications are essential for transforming activity. Replacement of the consensus sequence cysteine residue with other amino acids gives a ras protein that is no longer farnesylated, fails to migrate to the cell membrane and lacks the ability to stimulate cell proliferation (Hancock J. F., et al., Cell, 57:1167 (1989), Schafer W. R., et al., Science, 245:379 (1989), Casey P. J., Proc. Natl. Acad. Sci. USA, 86:8323 (1989)).
Recently, protein farnesyltransferases (PFTs, also referred to as farnesyl proteintransferases (FPTs) have been identified and a specific PFT from rat brain was purified to homogeneity (Reiss Y., et al., Bioch. Soc. Trans., 20:487-88 (1992)). The enzyme was characterized as a heterodimer composed of one alpha-subunit (49 kDa) and one beta-subunit (46 kDa), both of which are required for catalytic activity. High level expression of mammalian PFT in a baculovirus system and purification of the recombinant enzyme in active form has also been accomplished (Chen W. -J., et al., J. Biol. Chem., 268:9675 (1993)).
In light of the foregoing, the discovery that the function of oncogenic ras proteins is critically dependent on their post-translational processing provides a means of cancer chemotherapy through inhibition of the processing enzymes. The identification and isolation of a protein farnesyltransferase that catalyzes the addition of a farnesyl group to ras proteins provides a promising target for such intervention. Recently, it has been determined that prototypical inhibitors of PPT can inhibit ras processing and reverse cancerous morphology in tumor cell models (Kohl N. E., et al., Science, 260:1934 (1993), James G. L., et al., Science, 260:1937 (1993), Garcia A. M., et al., J. Biol. Chem., 268:18415 (1993)). Furthermore, Blaskovich M., et al., "Proceedings Eighty-Sixth Annual Meeting American Association For Cancer Research," Mar. 18-22, 1995, Toronto, Ontario, Canada, Vol. 86, March 1995, Abstract 2578, disclosed a series of tetrapeptide inhibitors of farnesyltransferase which inhibited growth of tumor cells in nude mice.
Nagasu T., et al., "Proceedings Eighty-Sixth Annual Meeting American Association For Cancer Research," Mar. 18-22, 1995, Toronto, Ontario, Canada, Vol. 86, March 1995, Abstract 2615, disclosed a peptidomimetic inhibitor, B956, of farnesyltransferase which inhibits growth of human tumor xenografts in nude mice. Kohl, N. E., et al., Proc. Natl. Acad. Sci. USA, 91:9141 (1994) have demonstrated that the protein farnesyltransferase inhibitor (L-739,749) blocks the growth of a ras-dependent tumor in nude mice. Sebti, S. M., et al., Cancer Research, 55:4243 (1995) have demonstrated that a farnesyltransferase inhibitor (FTI-276) blocks the growth in nude mice of a human lung carcinoma with a k-ras mutation. Inhibition of tumor growth is correlated with inhibition of ras processing.
Thus, it is possible to prevent or delay the onset of cellular proliferation in cancers that exhibit mutant ras proteins by blocking PFT. By analogous logic, inhibition of PFT would provide a potential means for controlling cellular proliferation associated with restenosis, especially in those cases wherein the expression and/or function of native ras is overstimulated. Indolfi, C., et al., Nature Medicine, 1:541 (1995) have demonstrated that inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in the rat.
PCT Published Patent Application WO91/16340 discloses cysteine containing tetrapeptide inhibitors of PFT of the Formula CAAX.
European Published Patent Application 0461869 discloses cysteine containing tetrapeptide inhibitors of PFT of the Formula Cys-Aaa.sup.1 -Aaa.sup.2 -Xaa.
European Published Patent Application 0520823 discloses cysteine containing tetrapeptide inhibitors of PFT of the Formula Cys-Xaa.sup.1 -dXaa.sup.2 -Xaa.sup.3.
European Published Patent Application 0523873 discloses cysteine containing tetrapeptide inhibitors of PFT of the Formula Cys-Xaa.sup.1 -Xaa.sup.2 -Xaa.sup.3.
European Published Patent Application 0528486 discloses cysteine containing tetrapeptide amides inhibitors of PFT of the Formula Cys-Xaa.sup.1 -Xaa.sup.2 -Xaa.sup.3 -NRR.sup.1.
European Published Patent Application 0535730 discloses pseudotetrapeptide inhibitors of PFT of the following two formulas: ##STR2##
Copending U.S. patent application Ser. No. 08/268,364 discloses a series of histidine and homohistidine derivatives as inhibitors of protein farnesyltransferase.
U.S. Pat. No. 4,870,183 discloses a series of amino acid derivatives of the Formula I: ##STR3## wherein Ar represents a phenyl group, a naphthyl group, or pyridyl group which may have a substituent. His represents an L-histidyl group, Y represents --O-- or --NH--, R represents a straight or branched chain alkyl group, a cycloalkyl group or a halogenated alkyl group, or pharmaceutically acceptable acid addition salts thereof, useful for treatment of hypertension, especially renin-associated hypertension. Additionally, U.S. Pat. No. 4,870,183 discloses intermediates of Formula IV: ##STR4## wherein the carbon atom marked with (S) is of S-- configuration and Ar is as defined above which are used to prepare compounds of Formula I.
U.S. Pat. No. 4,904,660 discloses a series of histidine derivatives useful as renin inhibitors in the treatment of hypertension. Additionally, U.S. Pat. No. 4,904,660 discloses intermediates of formula ##STR5## wherein R.sub.1 is ##STR6## and R.sub.2 is ##STR7## which are used to prepare the target renin inhibitors.
Compounds disclosed in the above references do not disclose or suggest the novel combination of structural variations found in the present invention described hereinafter.
We have surprisingly and unexpectedly found that a series of substituted histidines are inhibitors of farnesyltransferase and thus useful as agents for the treatment of proliferative diseases such as, for example, cancer, restenosis, and psoriasis, and as antiviral agents.